Sun Yilu, Chen Qilei, Cui Wei, Chen Hubiao, Zhao Jia, Rong Jianhui
School of Chinese Medicine, Li Ka Shing Faculty of Medicine, The University of Hong Kong, 3 Sassoon Road, Pokfulam, Hong Kong, 999077, China.
School of Chinese Medicine, Hong Kong Baptist University, 7 Baptist University Road, Kowloon Tong, Hong Kong, 999077, China.
J Leukoc Biol. 2025 Feb 13;117(2). doi: 10.1093/jleuko/qiae167.
Dysregulation of brain innate immunity involving microglia is implicated in the pathology of neurological disorders including depression. Depression is a prominent medical challenge to global public health systems. Synthetic antidepressant drugs are limited by severe side effects. The present study aimed to identify the active compounds from the well-documented herbal medicine formula Banxia-Houpo decoction (BHD) and discover the underlying mechanisms for tuning microglia. We initially employed Liquid chromatography-mass spectrometry (LC-MS) profiling and network pharmacology analysis to predict the active compound-target interaction networks. We subsequently validated the potential active compounds and targets in a mouse model of corticosterone (CORT)-induced depression and postsynaptic microglia BV2 cells. As a result, 64 compounds were identified in the ethanolic Banxia-Houpo decoction extract and predicted to target 25 depression-related genes. Interestingly, the serotonergic synapse pathway received the highest enrichment score while 5-hydroxytryptamine receptor 1A (HTR1A) was targeted by 6 compounds (i.e. baicalein, luteolin, N-nornuciferine, roemerine, scutellarin, and 6-shogaol). In parallel assays, a six-compound combo (SCC) and Banxia-Houpo decoction markedly ameliorated the depressive-like behaviors in corticosterone-lesioned mice and well-protected highly differentiated (HD) PC12 cells against corticosterone challenge. Moreover, six-compound combo and Banxia-Houpo decoction effectively induced hydroxytryptamine receptor 1A expression in mice and postsynaptic microglia BV2 cells. Hydroxytryptamine receptor 1A antagonist WAY-100635 at 1 mg/kg/d via intraperitoneal injection attenuated the effects of six-compound combo and Banxia-Houpo decoction on the depressive behaviors in mice. These results suggest that six-compound combo might be a potential remedy against depression and other neurological disorders via targeting hydroxytryptamine receptor 1A in microglia.
涉及小胶质细胞的脑固有免疫失调与包括抑郁症在内的神经系统疾病的病理过程有关。抑郁症是全球公共卫生系统面临的一项重大医学挑战。合成抗抑郁药物存在严重副作用的局限性。本研究旨在从记载详尽的中药方剂半夏厚朴汤（BHD）中鉴定活性成分，并发现调节小胶质细胞的潜在机制。我们首先采用液相色谱 - 质谱（LC-MS）分析和网络药理学分析来预测活性化合物 - 靶点相互作用网络。随后，我们在皮质酮（CORT）诱导的抑郁症小鼠模型和突触后小胶质细胞BV2细胞中验证了潜在的活性化合物和靶点。结果，在半夏厚朴汤乙醇提取物中鉴定出64种化合物，并预测它们靶向25个与抑郁症相关的基因。有趣的是，血清素能突触途径获得了最高的富集分数，而5-羟色胺受体1A（HTR1A）被6种化合物（即黄芩素、木犀草素、N-去甲荷叶碱、罗默碱、黄芩苷和6-姜辣素）靶向。在平行实验中，六种化合物组合（SCC）和半夏厚朴汤显著改善了皮质酮损伤小鼠的抑郁样行为，并很好地保护了高分化（HD）PC12细胞免受皮质酮的攻击。此外，六种化合物组合和半夏厚朴汤有效地诱导了小鼠和突触后小胶质细胞BV2细胞中5-羟色胺受体1A的表达。腹腔注射1mg/kg/d的5-羟色胺受体1A拮抗剂WAY-100635减弱了六种化合物组合和半夏厚朴汤对小鼠抑郁行为的影响。这些结果表明，六种化合物组合可能通过靶向小胶质细胞中的5-羟色胺受体1A成为治疗抑郁症和其他神经系统疾病的潜在药物。
